Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• the present invention relates to certain 1-(naphthyl-n-propyl)imidazole derivatives. More particularly, the present invention relates to compounds of formula (I), namely: ##STR2## wherein Z is hydroxymethylene, esterified hydroxymethylene, C 1 to C 4 alkoxymethylene, carbonyl, of ketal-protected carbonyl; and the pharmaceutically acceptable acid addition salts thereof.
• esterified hydroxymethylene refers to a hydroxymethylene group which has been esterified with an alkanoic acid having from 1 to 8 carbon atoms or with benzoic acid. Typical alkanoic acids which may be mentioned are formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid and octanoic acid.
• alkoxymethylene refers to a hydroxymethylene group which has been alkylated on oxygen with a straight or branched chain group having from 1 to 4 carbon atoms.
• ketal-protected carbonyl refers to (i) a carbonyl group protected as an acyclic ketal derived from a monohydric straight chain alkanol having from 1 to 4 carbon atoms such as, for example, the dimethyl-, diethyl-, di(n-propyl)-and di(n-butyl)ketals, and (ii) a carbonyl group protected as a cyclic ketal derived from a dihydric alcohol having 2 or 3 carbon atoms which may optionally be substituted by one or more methyl groups, for example, the ethylenedioxy-, 1,3-propylenedioxy-, 1,2-propylenedioxy-, 2,2-dimethyl-1,3-propylenedioxy-, 1-methyl-1,3-propylenedioxy-, 1,3-dimethyl-1,3-propylenedioxy-, 1,3-dimethyl-1,3-propyl
• salts refers to salts of the free bases of formula (I), which salts possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable.
• Such salts may be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.
• compounds of formula (I) wherein Z is hydroxymethylene, esterified hydroxymethylene or alkoxymethylene may be prepared in optically active form by conventional resolution means known per se, for example, by the separation (e.g., fractional crystallization) of the diastereomeric salts formed by reaction of, e.g., racemic compounds of formula (I) wherein Z is hydroxymethylene or esterified hydroxymethylene, or alkoxymethylene with an optically active acid, or by separation of the diastereomeric esters formed by reaction of such a racemic alcohol wherein Z is hydroxymethylene with an optically active acid.
• optically active acids are the optically active forms of camphor-10-sulfonic acid, ⁇ -bromocamphor- ⁇ -sulfonic acid, camphoric acid, menthoxyacetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid, and the like.
• the separated pure diastereomeric salts or esters may then be cleaved by standard means to afford the respective optical isomers of the desired compound.
• Compounds of formula (I) exhibit a broad spectrum of CNS related activity such as anticonvulsant activity (as demonstrated by the maximal electroshock seizure test), anorexigenic, antidepressant and muscle relaxing activity; as well as activity of other types such as inhibition of gastric secretion, antihypertensive and spermatostatic/spermatocidal activities.
• One aspect of the present invention relates to a method for treating and/or preventing convulsions in a mammalian subject comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof.
• Another aspect of the present invention relates to pharmaceutical compositions useful for the treatment and/or prevention of convulsions in a mammalian subject comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable non-toxic carrier.
• a pharmaceutically acceptable non-toxic carrier for this utility compounds of formula (I) wherein Z is carbonyl, ketal-protected carbonyl or alkoxymethylene are particularly preferred.
• a therapeutically effective amount of the compound of formula (I) or a pharmaceutical composition containing same is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents.
• These compounds or compositions can thus be administered orally or parenterally (i.e. intramuscularly, subcutaneously and intraveneously), and can be administered either in the form of solid or liquid dosages including tablets, solutions, suspensions, and the like, as discussed in more detail hereinbefore. Oral administration is preferred.
• the administration can be conducted in a single unit dosage form the continuous therapy or in single dosage therapy ad libitum.
• the method of the present invention may be practiced when relief of symptoms is specifically required, i.e. therapeutically, or as continuous or prophylactic treatment.
• the effective dosage in accordance herewith can vary over a wide range.
• a therapeutically effective amount for anticonvulsant use ranges from about 0.1 to about 300 mg./kg. body weight per day.
• a therapeutically effective amount in accordance herewith would be, in preferred embodiments, from about 70 mg. to about 7 g per day per subject.
• a therapeutically effective amount for inhibition of gastric secretion ranges from about 0.1 to about 300 mg./kg. body weight per day and preferably from about 0.25 to about 100 mg./kg. body weight per day.
• a therapeutically effective amount in accordance herewith would be, in preferred embodiments from about 18 mg. to about 7 g per day per subject.
• compositions hereof can be solids or liquids.
• the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, and the like.
• Carriers can be selected from the various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions.
• Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
• Suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will, in any event, contain a therapeutically effective amount of the active compound together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the subject.
• the compounds of the present invention may be prepared according to methods well known in the art.
• compounds of formula (I) wherein Z is carbonyl may be prepared in a manner analogous to that described in U.S. Pat. No. 4,078,071 to the applicant for the corresponding phenyl compounds.
• This method comprises reacting a haloethyl naphthyl ketone, or a vinyl naphthyl ketone or the Mannich base quaternary intermediate thereof with imidazole in an inert organic solvent.
• the starting haloethyl naphthyl ketones are known or may be prepared by the Friedel-Crafts reaction of naphthalene with ⁇ -chloropropionyl chloride.
• Vinyl ketones insofar as they may not be known or generally available, may be prepared by a variety of methods well known in the synthetic organic chemistry art, for example, by the addition of vinyl lithium to the corresponding carboxylic acid; by the addition of vinyl lithium to the corresponding aldehyde followed by oxidation of the allylic alcohol thus produced to the vinyl ketone (e.g., J. Chem. Soc (C), 1966, p. 1972; J. Chem Soc. (London), 1956, p. 3070); or by Mannich reaction of the corresponding methyl ketone, quaternization and elimination.
• the preparation of ketones of formula (I) by the above described method may be carried out in an inert organic solvent, for example, dimethylformamide at a temperature between about -10° and +40° C.
• Preparation of compounds of formula (I) wherein Z is hydroxymethylene may be accomplished by the reduction of the corresponding ketone or acid addition salt thereof under standard conditions, for example, by the use of sodium tetrahydroborate in a protic solvent, for example, methanol, at a temperature between about -20° and +20° C.
• a protic solvent for example, methanol
• Compounds of formula (I) wherein Z is esterified hydroxymethylene may be prepared under usual esterification conditions from the corresponding alcohol by treatment of the alcohol with the desired acid halide or anhydride in the presence of a base, preferably a tertiary amine such as pyridine or triethylamine, at a temperature between about 0° and +40° C. in a solvent such as pyridine, tetrahydrofuran, dichloromethane, chloroform, and the like.
• a base preferably a tertiary amine such as pyridine or triethylamine
• the naphthyl haloethyl ketone is first converted to the halo ketal (II).
• Ketalization to form cyclic ketals may be performed by methods well known in the art, e.g. by treatment of the ketone with the desired dihydric alcohol in the presence of a strong acid, for example a sulfonic acid such as p-toluene-sulfonic acid or a Lewis acid such as boron trifluoride.
• Water is preferably removed as an azeotrope with the solvent, for example an aromatic hydrocarbon such as benzene or toluene, at a temperature sufficient to effect such azeotropic removal, e.g. from about 75° to about 150° C.
• Ketalization to form acyclic ketals may be performed by employing an orthoester (e.g. methyl orthoformate or ethyl orthoformate) in the presence of an acid or Lewis acid, e.g. boron trifluoride, p-toluenesulfonic acid, perchloric acid, fuming sulfuric acid, and the like.
• an acid or Lewis acid e.g. boron trifluoride, p-toluenesulfonic acid, perchloric acid, fuming sulfuric acid, and the like.
• the haloketal (II) is then converted to (I) by treatment with imidazole in a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide acetonitrile or tetrahydrofuran at a temperature between about 20° and 130° C.
• Compounds of formula (I) wherein Z is alkoxymethylene may be prepared by alkylation of the corresponding alcohols.
• the alkylation is carried out by converting the alcohol to a metal salt, preferably an alkali metal salt, by treatment with a strong base such as, for example, an (alkali) metal hydride such as sodium hydride or an (alkali) metal amide such as sodium amide or potassium amide and the like.
• a strong base such as, for example, an (alkali) metal hydride such as sodium hydride or an (alkali) metal amide such as sodium amide or potassium amide and the like.
• This is preferably done in an inert organic solvent such as dimethylformamide, hexamethylphosphoramide, tetrahydrofuran and the like.
• the (alkali) metal salt is then contacted with an alkylating agent, e.g.
• an alkyl halide, sulfate or sulfonate ester preferably an alkyl halide, preferably in the same solvent system, at a temperature between -20° and 100° C., most preferably between 0° and 60° C., for a period of 30 minutes to 18 hours.
• the subject compounds of formula (I) can be isolated as free bases; however, since many of the compounds in base form are oils and gums and/or not water soluble it is often more convenient to isolate and further characterize such compounds as acid addition salts.
• These salts are prepared in the usual manner, i.e., by reaction of the free base with a suitable inorganic or organic acid, for example one of the pharmaceutically acceptable acids described above. If desired, the salt can be readily converted to the free base by treatment with a base such as potassium or sodium carbonate or potassium or sodium hydroxide.
• a further aspect of the present invention concerns a process for the preparation of a free base compound of the formula ##STR4## wherein Z is hydroxymethylene, esterified hydroxymethylene, (C 1 to C 4 ) alkoxymethylene, carbonyl, or ketal-protected carbonyl; or a pharmaceutically acceptable non-toxic acid addition salt thereof, which process comprises:
• the crude salt (11.3 g) is recrystallized from methanol/acetone to yield colorless crystals of 1-[2-(2-naphthoyl)ethyl]imidazole hydrochloride, m.p. 182.5°-186° C.
• the resulting colorless oil crystallizes on addition of ether and scratching, and is recrystallized from ethyl acetate to give 2.4 g of 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole.
• the hydrochloride salt is prepared by treatment of an ethereal solution of the free base with ethereal hydrogen chloride until precipitation is complete. The precipitate is collected and recrystallized from methanol/acetone to give 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole hydrochloride, m.p. 166.7°-168.1° C.
• a solution of 1.2 g of 1-[3-hydroxy-3-(2-naphthyl)-n-propyl]imidazole in 20 ml of dry hexamethylphosphoramide is treated between 5°-10° C. with stirring under nitrogen with 0.24 g of a 50% dispersion of sodium hydride in mineral oil. The mixture is stirred one hour at 10° C., one hour at 50° C., and then cooled in ice. Methyl iodide (0.8 g.) in 2 ml of hexamethylphosphoramide is added with stirring maintaining the temperature below 10° C. and the mixture stirred at 5° C. for 1 hour and overnight at room temperature.
• all compounds of formula (I) in free base form may be converted to the acid addition salts by treatment with the appropriate acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.
• the appropriate acid for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tarta
• compositions for oral administration which may be prepared for the compounds of the present invention, e.g.
• the above ingredients are combined and granulated using methanol as the solvent.
• the formulation is then dried and formed into tablets (containing 200 mg of active compound each) with an appropriate tabletting machine.

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• 1979
  • 1979-03-09 US US06/019,201 patent/US4293561A/en not_active Expired - Lifetime
• 1980
  • 1980-03-04 CA CA000346989A patent/CA1134368A/en not_active Expired
  • 1980-03-06 EP EP80300681A patent/EP0015750B1/de not_active Expired
  • 1980-03-06 AT AT80300681T patent/ATE1859T1/de not_active IP Right Cessation
  • 1980-03-06 DE DE8080300681T patent/DE3061125D1/de not_active Expired
  • 1980-03-08 ES ES489354A patent/ES8104239A1/es not_active Expired
  • 1980-03-10 JP JP3020980A patent/JPS55162777A/ja active Pending

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